Syphilis is a chronic bacterial infection which, after five centuries, continues to plague individuals worldwide. Although effective therapy has been available for fifty years, the United States is currently in the midst of a syphilis epidemic, with a 50% increase in incidence in the past two years. In addition to the serious late sequelae of syphilis, numerous studies suggest that syphilis and other genital ulcer diseases may be risk factors for acquisition and transmission of human immunodeficiency virus (HIV) infection. The immune response to syphilis infection has been under investigation for a number of years, however a clear understanding of the specific mechanisms of resistance has not yet been achieved. Antibody, which is produced in high titer during infection, can neutralize, immobilize, and opsonize T. pallidum, yet its importance in lesion resolution and resistance is unknown. Based upon histological and laboratory studies, it is generally accepted that the cellular arm of the immune system is central to the clearance of syphilitic lesions and the development of resistance. Our working hypothesis of syphilis immunity centers around the production of lymphokines (macrophage activating factors [MAF], including gamma-interferon) by specifically sensitized lymphocytes with the resultant activation of effector macrophages which are primarily responsible for bacterial clearance. Although a number of Treponema pallidum antigens have been identified and characterized in terms of antibody reactivity, little is known about the antigens which induce cellular immune responses. In order to focus future vaccine studies on molecules which are known to stimulate the specific cellular functions believed to be central to syphilis immunity, this renewal application proposes the examination of individual antigens of T. pallidum in terms of their interaction with macrophages and lymphocytes in the induction and development of these cellular responses. Specifically, we propose 1) the identification of antigenic molecules and peptides of T. pallidum which stimulate production of macrophage activating factors (MAF) by sensitized lymphocytes in vitro and induce delayed hypersensitivity in vivo 2) the examination of the nature of antigen processing and kinetics of presentation of individual antigens by macrophages in order to characterize molecules and determinants which readily induce appropriate T lymphocyte responses; 3) the development of T cell clones with specificity for T. pallidum antigens for use in antigen presentation assays and for examination of lymphokine production in response to individual T cell epitopes; 4) the immunization of rabbits with T. pallidum antigens incorporated into liposomes; and 5) the examination of the parameters of phagocytosis of T pallidum and the effector function of macrophages on T. pallidum. We anticipate that these studies will aid in the understanding of the mechanisms of immunity to T. pallidum and will identify specific antigens or epitopes which stimulate protective cellular immune functions.